Targeted infusion of agents for treatment of ALS

ABSTRACT

A system and method for treating Amyotrophic Lateral Sclerosis (ALS) by delivery of an agent within the brain. At least one image of a target region is acquired, and at least one magnetic resonance diffusion tensor imaging (MR-DTI) scan of the target region is acquired. A diffusion tensor is calculated from the at least one MR-DTI scan, and at least one of an agent distribution and an agent concentration from the images and the calculated diffusion tensor is calculated. Using at least one of the calculated diffusion tensor, the images, the calculated agent distribution, and the calculated agent concentration, the placement of a delivery instrument is planned to deliver the agent to the target region to achieve a desired agent concentration and/or agent distribution within the target region.

RELATED APPLICATION DATA

This application claims priority of U.S. Provisional Application No.60/619,119 filed on Oct. 15, 2004, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to treating Amyotrophic LateralSclerosis (ALS) and, more particularly, to treating ALS using a plannedtargeted delivery of therapeutic substances within the brain and aplanned placement of catheters within the brain.

BACKGROUND OF THE INVENTION

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative diseasethat attacks nerve cells in the brain and the spinal cord, andultimately is fatal. Motor neurons reach from the brain to the spinalcord and from the spinal cord to the muscles throughout the body. As themotor neurons degenerate, they can no longer send impulses to the musclefibers that provide muscle movement. The progressive degeneration of themotor neurons in ALS eventually leads to their death. When the motorneurons die, the ability of the brain to initiate and control musclemovement is lost. With all voluntary muscle action affected, patients inthe later stages of the disease become totally paralyzed. However, forthe vast majority of people their minds remain unaffected.

Early symptoms of ALS often include increasing muscle weakness,especially involving muscles in the arms and legs, and in musclesrelated to speech, swallowing and breathing. When the muscles no longerreceive messages from the motor neurons, the muscles begin to atrophy(waste away).

There are several approaches to treating ALS and its symptoms. However,the only FDA approved medication is Riluzol (Rilutek), which isadministered systemic. Riluzol is neuro-protective and inhibits thepre-synaptic release of glutamate, the most important neurotransmitter,and influences the activation of sodium channels. However, systemicadministration of neurotropic growth factors is limited due to sideeffects and to the limited control to gain a specific concentration ofeffective agents in the target region. Other treatments for ALS involveneurotrophic growth factors or combination therapies with agents fromdifferent families of neurotrophic growth factors and/or Riluzol and/oranti-oxidants (e.g., vitamin E).

Recent studies imply the importance of influencing the localconcentration of neurotropic growth factors in the central nervoussystem. Therefore, the agents can be infused directly to target regionsor into the cerebrospinal fluid.

Methods of administering a drug or other material to a target part ofthe body are known in the art. For example, U.S. Pat. No. 6,026,316discloses a method for targeted drug delivery into a living patientusing magnetic resonance (MR) imaging. The method uses MR imaging totrack the location of drug delivery and estimate the rate of drugdelivery. More particularly, an MR-visible drug delivery device ispositioned at a target site to deliver a diagnostic or therapeutic drugsolution into the tissue. The spatial distribution kinetics of theinjected or infused drug agent are monitored quantitatively andnon-invasively using water proton directional diffusion MR imaging toestablish the efficacy of drug delivery at a targeted location.

U.S. Pat. No. 5,720,720 discloses a method of high-flow microinfusionthat provides convection-enhanced delivery of agents into the brain andother solid tissue structures. The method involves positioning the tipof an infusion catheter within a tissue structure, and supplying anagent through the catheter while maintaining a pressure gradient fromthe tip of the catheter during infusion. The method can be used todeliver various drugs, protein toxins, antibodies for treatment orimaging, proteins in enzyme replacement therapy, growth factors in thetreatment of various neurodegenerative disorders and viruses and genetherapy.

U.S. Pat. No. 5,735,814 discloses techniques for infusing drugs into thebrain to treat neurodegenerative disorders by an implantable pump andcatheter. The drugs are capable of altering the level of excitation ofneurons in the brain. A sensor is used to detect an attribute of thenervous system which reflects the hyperexcitation of the nerve cellsprojecting onto the degenerating nerve cells, and a microprocessoralgorithm analyzes the output from the sensor in order to regulate theamount of drug delivered to the brain.

Finally, U.S. Pat. No. 6,549,803 discloses the movement of material inan organism, such as a drug injected into a brain. The movement ismodeled by a uniformly structured field of static constants governingtransport by moving fluid and diffusion within the fluid. This supportsplanning of material introduction, (e.g., infusion, perfusion,retroperfusion, injections, etc.) to achieve a desired distribution ofthe material, continuing real-time feedback as to whether imagedmaterial is moving as planned and will be distributed as desired, andreal-time plan modification to improve results.

SUMMARY OF THE INVENTION

The above discussed prior art discloses techniques for infusing drugsinto the brain. The above prior art, however, does not disclose treatingALS using a planned targeted delivery of a therapeutic substance to thebrain. The present invention provides such a planned targeted deliveryof a therapeutic substance to the brain for the effective treatment ofALS. Additionally, the effectiveness of the plan can be analyzed priorto performing the treatment.

According to one aspect of the invention, there is provided a system andmethod for treating ALS by delivery of an agent within the brain,wherein a target region of the brain can be identified and a delivery byinfusion of the agent to the target region of the brain can be planned.

According to another aspect of the invention, there is provided a systemand method for treating ALS, wherein at least one image of a targetregion and at least one magnetic resonance diffusion tensor imaging(MR-DTI) scan of the target region may be acquired. A diffusion tensorcan be calculated from the at least one MR-DTI scan, and at least one ofan agent distribution and an agent concentration can be calculated fromthe images and the calculated diffusion tensor. At least one of thecalculated diffusion tensor, the images, the calculated agentdistribution, and the calculated agent concentration can be used to planthe placement of a delivery instrument to deliver the agent to thetarget region to achieve a desired agent concentration and/or agentdistribution within the target region.

To the accomplishment of the foregoing and related ends, the invention,then, comprises the features hereinafter fully described andparticularly pointed out in the claims. The following description andthe annexed drawings set forth in detail certain illustrativeembodiments of the invention. These embodiments are indicative, however,of but a few of the various ways in which the principles of theinvention may be employed. Other objects, advantages and novel featuresof the invention will become apparent from the following detaileddescription of the invention when considered in conjunction with thedrawings.

The forgoing and other embodiments of the invention are hereinafterdiscussed with reference to the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a navigation system that can be used inconjunction with the present invention.

FIG. 2 is a flow diagram for predicting the concentration and/ordistribution of an agent in accordance with an embodiment of theinvention.

FIG. 3 is a block diagram of a computer system that can be used toimplement the method of the present invention.

DETAILED DESCRIPTION

In general, the term “infusion” is to be understood in accordance withthe invention as any administration of a liquid, vapor or solidsubstance and/or an infusing medium such as medicines, cells, genes,enzymes, proteins, antibodies, hormones, viruses or the like, e.g.,viral vectors and viruses such as Adeno-associated virus systems, intobody tissue, as opposed to systemic administration of an agent. Thesubstances are introduced directly into body tissue in order to surmounta barrier, such as the blood-brain barrier, for example. The substancescan be delivered within a relatively short period of time (e.g., via aninjection), or over a longer period of time (e.g., via a continuousand/or variable rate of delivery of the substance). Methods foradministering a substance are described in commonly owned U.S. patentapplication Ser. No. 10/075,108, the entire contents of which is herebyincorporated by reference.

In performing infusion of agents to treat ALS, certain recommendedguidelines should be followed. For example, to minimize backflow of theagent along a trajectory of a catheter, the diameter of the catheterlumen should be less than 1.5 millimeters. Alternatively, a speciallydesigned catheter that has varying diameters along its length can beimplemented, e.g., a tapered catheter. To keep the backflow less than 3centimeters, the flow rate of the delivered agent should be less thanabout 7 micro liters per minute.

A method for targeted infusion of agents in the brain to treat ALS isprovided. As used herein, an “agent” or “agents” to be infused includestherapeutic substances such as, for example, neuro-protective substancesthat inhibit pre-synaptic release of glutamate and/or influence theactivation of sodium channels, antioxidants, and any other agent usefulfor treating ALS through targeted infusion. Riluzol is an example of anagent that can be used in accordance with the present invention.

Patient data and/or patient parameters of the brain are acquired and/orcalculated prior to administering the agents. Patient data and/orparameters relating to the brain can be obtained using known techniques,including, for example, magnetic resonance (e.g., dynamiccontrast-enhance magnetic resonance imaging, magnetic resonanceperfusion imaging) or nuclear spin resonance methods (MRI), computertomography (CT), positron emission tomography (PET), single photonemission computerized tomography (SPECT), biopsy, x-rays and/orultrasound. Additionally, other suitable methods that enable the spatialstructure of a body and/or a tissue structure (e.g., the brain) to bedetected and viewed can be used. In addition to the above imagingtechniques, patient parameters such as, for example, tissue density, thedistribution of tissue structures, and/or the blood flow through aparticular area of tissue, also can be obtained from known data oftypical specimens and/or measured using other accepted medicalprocedures. Such data can be stored in a database, for example.

Once the patient data has been obtained, mathematical models are appliedto the data to extract relevant information. Sources (catheters) andsinks (non-intact blood-brain barrier, outflow through sulcii, outflowfrom cortical surface, binding to cells, etc.) as well as individualanatomy and physiology and catheter positions are considered in modelingthe concentration and distribution of the agents. More specifically,data relating to diffusivity, pathways, nerve tracks, conductivity,fluid conductivity, pressure, etc., are extracted from the images and/orother measurements. Using the data, a calculation is made of thepossible distribution of the agents and/or the possible concentration ofthe agents in the target region. In performing the calculations, theextracted information is related to flow (transport mechanisms), efflux(permeability, blood-brain barrier), diffusion (transport mechanisms),conductivity and anatomical (white/grey matter) information.Furthermore, chemical, pharmaceutical and/or biological properties ofeach agent can be used in the calculations, thereby increasing thespecificity of the calculations.

The calculations can be performed, for example, using a computer toexecute code that calculates the agent concentration and/or the agentdistribution based on known properties of the agent and/or the targetregion. The computer can provide the results of the calculations via acomputer display, for example.

Once the concentration and/or distribution of the agent is determined,the data can be displayed or otherwise reported to medical personnel forevaluation. This can be performed, for example, via a simulationpresented on the computer display. More specifically, two-dimensionaland/or three-dimensional images of the target region can be viewed onthe computer display, along with the expected or calculatedconcentration and/or distribution of the agent in the target region.

Should the results (e.g., the concentration and/or distribution of theagent) be unsatisfactory, i.e., they do not meet established orotherwise desired criteria for the procedure, then the plan is refinedand re-evaluated until a satisfactory plan can be obtained. If, on theother hand, the results are satisfactory, then the plan can be saved andtransferred to a navigation system for execution of the plan.

Referring initially to FIG. 1, a medical navigation system 2 that can beused in conjunction with the present invention is illustrated.Navigation systems of various types are well known in the art andtherefore will not be discussed in detail herein. Briefly, and by way ofexample, pre-operative images and/or operative images of a patient 4 areprovided to a computer controller 6. The patient 4 is placed on anoperating table 8, and a reference star 10 or other suitable trackabledevice is rigidly fixed to an area of interest of the patient, e.g. thecranium. The reference star 10 can include passive and/or activeelements 10 a that are detectable by at least two cameras 12 or otherdetection apparatus. The cameras 12 ascertain the spatial position ofthe reference star 10 and, therefore, the spatial position of the areaof interest, and provide the spatial information to the computercontroller 6 via a wired or wireless communications link 14.

Prior to displaying the patient's pre-operative or operative images, thepatient 4 is registered into the navigation system 2. Registration isthe process of teaching the computer controller 6 the location of thearea of interest on the patient with respect to the reference star 10and correlating the patient location to previously obtained data. Thiscan be done, for example, by indicating to the computer controller 6 thelocation of several points on the patient 4 using an instrument 16, suchas a probe, for example, having active or passive elements 10 a thereon.Provided the computer controller 6 knows the geometry of the instrument16, the computer controller can ascertain the location of a tip 16 a ofthe instrument. By placing the tip 16 a of the instrument on severalpoints on the patient 4, the computer controller 6 can ascertain thespatial position of the area of interest with respect to the referencestar 10 and correlate the preoperative and/or operative images to thearea of interest, thereby completing registration. Once registered, thecomputer controller 6 displays the images on one or more displays 18 viaa video link 18 a. Those skilled in the art will appreciate that theregistration process can be performed in other ways.

As the patient 4 is moved on the table 8, the images displayed on thedisplay 18 also move so as to always show the images with the correctpositional relationship. Moreover, one or more instruments 16, such as acatheter, a probe, etc., also can be displayed on the display 18,provided the geometry of each instrument is known by the computercontroller 6. A known navigation system is VectorVision™, available fromBrainLAB AG, and described, for example, in U.S. Patent Publication No.2003/0225329, which is hereby incorporated by reference.

Referring now to FIG. 2, a flow diagram 50 illustrating a method inaccordance with an embodiment of the invention is provided. The flowdiagram includes a number of process blocks arranged in a particularorder. As should be appreciated, many alternatives and equivalents tothe illustrated steps may exist and such alternatives and equivalentsare intended to fall with the scope of the claims appended hereto.Alternatives may involve carrying out additional steps or actions notspecifically recited and/or shown, carrying out steps or actions in adifferent order from that recited and/or shown, and/or omitting recitedand/or shown steps. Alternatives also include carrying out steps oractions concurrently or with partial concurrence.

Beginning at step 52, the target region is determined and/or outlined.For example, it may be known through literature, experience or previousdiagnostic tests that a certain region of the brain is responsible foror is affected by ALS, e.g., the hippocampus. Thus, this region can besaid to be the target region. If applicable, the target region can beidentified by measuring electrical activity from the cells in an area ofinterest. Cell types having the same amount or type of electricalactivity can be classified as the same cell type. The same cell typescan be grouped together and classified as the target region, asindicated in alternative steps 52 a-52 c.

For example, certain cell types may be known to exhibit a certain amountof electrical activity, while other cell types may exhibit differentamounts or different types of electrical activity. As used herein,electrical activity refers to at least one or more of an impedance, ashape of an electrical waveform, an amplitude of the electricalwaveform, a frequency of the electrical waveform, or other electricalproperties. By monitoring the electrical activity of the cells,different cell types belonging to different tissue regions or abnormalcells can be identified. Based on knowledge obtained from monitoringelectrical activity of different cells, a desired target region can beidentified and clearly delineated from surrounding cells or regions.

Electrical activity can be monitored by placing measurement electrodeson a catheter or probe and inserting the probe into or near the targetregion. The measurement electrodes detect the electrical activity and,via a wired or wireless communication link, provide the electrical datato the computer controller 6. The computer controller 6 can analyze thedata and establish a pattern for the cell types. Based on apredetermined criteria, e.g., the shape of the waveform, the frequencyof the waveform, the amplitude of the waveform, known electricalactivity from various regions of the brain, etc., the computercontroller 6 can distinguish between different cell types and identifythe target region.

Once the target region is determined and/or outlined, with or withoutthe above described procedures, an initial trajectory for a deliveryinstrument, e.g., a catheter, is planned (catheter planning), asindicated at step 54. The initial trajectory can be based on knowledgeand/or experience with a particular procedure, accepted practices bythose skilled in the art, recommendations by medical experts and/ormedical societies, or any other criteria accepted by those skilled inthe art. According to one embodiment, multiple catheters are used toensure coverage of the entire target area.

Next, at step 56 three-dimensional images of the target region areobtained using any one of several imaging techniques, e.g., MRI, CT,PET, SPECT, etc. The three dimensional images of the target region canbe automatically segmented so as to present internal or partial views ofthe target region as is conventional. For proper identification of thetarget region (hippocampus), it is preferable to obtain a highresolution MR-T1 image of the target region. According to oneembodiment, high resolution MRI scans having at least 1 millimeterin-plane spatial resolutions are obtained of the target region.Additionally, further images can be obtained relating to the anatomyand/or physiology of the patient and/or the target region. Theadditional images can be obtained using the above mentioned imagingtechniques. Such data can be used to identify tissue density and bloodflow through a particular area of tissue, for example.

Moving to step 58, MR-DTI scans are acquired of the target region. As isknown by those skilled in the art, MR-DTI uses water diffusion to obtainstructural information about the brain. MR-DTI can reveal properties ofthe brain that are not accessible through standard structural MRimaging. Using the MR-DTI scans, the diffusion tensor for the targetregion is calculated as indicated at step 60.

For example, a 3×3 matrix can represent the diffusion tensor. This maybe accomplished with six independent elements. It generally is agreed inthe art that at least three directions of the diffusion weightinggradient (which are independent of the preferred directional diffusion)should be sampled to generate trace images. These trace images are thesum of the diagonal elements of the diffusion tensor. Further, a minimumof 6 directions should be sampled for each voxel, if the full diffusiontensor is to be evaluated.

The MR signal of the scan depends on both the direction and magnitude ofa diffusion weighting gradient. Through combinations of the x, y, and zgradients, the MR signal can be sensitized to the component of diffusionin any arbitrary direction. The diffusion tensor can be calculated, forexample, by obtaining measurements with diffusion weighting gradients inat least six non-collinear directions (since the symmetric tensor itselfas six independent components) as well as with no diffusion weighting.In practice, many more directions may be measured, and a fittingprocedure can be used to calculate the six tensor components for eachvoxel.

The distinct structure of the hippocampus requires special imagingparameters for the MR-DTI scans. It is preferable to use a matrix sizeof 128², and more preferable to use a matrix size of 256². Additionally,the slice thickness of the images should be below 3 millimeters and gapsbetween slices should be avoided to allow proper three-dimensionalreconstruction.

Based on the above acquired data, e.g., MRI, MR-DTI, diffusion tensor,etc., the agent distribution and/or the agent concentration in thetarget region are calculated as indicated at step 62. More specifically,data relating to diffusivity, pathways, nerve tracks, etc., areextracted from the images and/or measurements. The extracted informationthen is related to flow (transport mechanisms), efflux (permeability,blood-brain barrier), diffusion (transport mechanisms), conductivity andanatomical (white/grey matter) information to predict possibledistribution of the agents and/or possible concentration of the agentsin the target region.

For example, and as was noted above, the three dimensional images of thetarget region can be automatically segmented so as to present internalor partial views of the target region. Anatomical data can be segmentedinto clusters of similar anatomical and/or physiological properties suchas bone, tissue, tissue/vascular system and spinal cord/brain. Next,hydraulic properties and/or vascular or other permeability properties ofeach cluster can be determined from the obtained anatomical and/orphysiological data. Nerve fibers can be tracked by interpreting localvariations of diffusivity to determine pathways of nerves in the brainclusters. The determined nerve pathways also can be used to derive thetarget regions.

In making the above calculations, the blood-brain barrier disruption isassumed to be negligible, so efflux or influx from/to the vascularsystem of the target region can be neglected. Additionally, perfusion ordynamic T1 data acquisition is not necessary, although they may beapplied to determine local variations of vascular permeability, vascularinflux or vascular efflux from distinct regions of the target region.

Local variations in pore fraction can be derived from identificationand/or segmentation of gray and white matter structures applying knownvalues from the literature. Alternatively, multiple b-value MR-DTI scanscan be applied to estimate pore fraction or b0 or T2 images from MRIscans can be used to estimate pore fraction.

Chemical, pharmaceutical and/or biological properties of each agent alsocan be applied in the above calculations. More specifically, parametersof the agent that characterize the substance to be administered and/ordefine the physical, chemical and/or biological properties of the agentcan be used. The parameters can relate to a molecular or particle sizeof the substance to be administered, a rate of diffusion of thesubstance in a particular type of tissue, a metabolism and/orinteraction of the substance with tissue due to metabolic processes, adiffusion coefficient known for the substance for the type of tissue tobe treated, a preferred injection pressure or pressure gradient, apreferred concentration of the substance, and/or the quantity or rate ofdelivery. Such data can be stored and retrieved from a database residingon the computer controller 6, for example.

It is noted that should the flow rate of the agent reach zero, thenthere is no convection, leaving only diffusion as the driver for thedistribution process. In such a case, the mathematical model may beadjusted to only use diffusion to calculate agent distribution andconcentration (e.g., a model based on the magnetic resonance diffusiontensor imaging (MR-DTI) data and anatomical/physiological data).

Moving to step 64, the acquired data (e.g., the image scans) and thecalculated data are combined and used to perform a simulation of theplanned infusion. The simulation also can be based on infusion withrespect to the individual anatomical environment and/or to chemical andphysical properties of the infused agent. Using a simulation, the agentconcentration and/or the agent distribution in the target region can bedetermined statistically and dynamically as a function of time. Thus, itcan be established prior to the actual procedure whether the desiredagent concentration and agent distribution will be achieved.

For example, and as was noted previously, the images of the targetregion can be viewed on a computer display and the calculated data,e.g., the expected agent concentration and/or the expected agentdistribution, can be included with and/or superimposed on the imagescans. By accurately rendering the agent concentration and/or the agentdistribution in the target region on the actual images of the targetregion, medical personnel can visually observe the results of the plan.

Medical personnel, depending on the outcome of the simulation, candetermine whether the results are satisfactory or whether furtherplanning is required, as indicated at step 66. Alternatively, thecomputer controller 6 can provide an indication as to whether theplanned infusion meets certain specified criteria and, subject toacceptance by medical personnel, the plan can be implemented. If theplan is acceptable, the plan is saved and executed by the navigationsystem 2, as indicated at step 70.

According to one embodiment, guidelines are presented to the medicalpersonnel during execution of the plan. For example, the guidelines maypresent information relating to recommended depths of the catheter orstimulation probe and/or to recommended geometric relations regardingspecific anatomical structures.

If the plan is not acceptable, then the plan is refined at step 68 andthe process moves back to step 62. The plan can be refined, for example,by changing one or more of the planned depth of the delivery instrumentinto the target region, the planned entry angle of the deliveryinstrument, the flow rate of the agent, the amount of agent introducedin the target region, or any other parameter related to delivery of theagent or the agent itself. According to one embodiment, the computercontroller 6 presents alternate catheter positions and/or alternate flowrates. The alternate flow rates, for example, can be based on catheterposition and/or the specifics of the anatomy and physiology of thetarget region, as indicated in steps 68 a and 68 b. The computercontroller can be provided with an initial plan and the computercontroller 6, using the initial plan, can determine a location and/ordelivery of the agent that satisfies a predetermined criteria.

The above described method can be implemented using the computercontroller 6 of the navigation system 2 (described in more detailbelow), or another computer not associated with the navigation system.Additionally, it is noted that the invention can be implemented to befully automatic, e.g., using data and/or parameters stored in adatabase, semi-automatic, e.g., selections displayed on a menu are madeby an operator, or manual, e.g., values are input by an operator.

Moving to FIG. 3, a computer controller 6 for executing a computerprogram in accordance with the present invention is illustrated. Thecomputer controller 6 includes a computer 72 for processing data, and adisplay 74 for viewing system information. The technology used in thedisplay is not critical and may be any type currently available, such asa flat panel liquid crystal display (LCD) or a cathode ray tube (CRT)display, or any display subsequently developed. A keyboard 76 andpointing device 78 may be used for data entry, data display, screennavigation, etc. The keyboard 76 and pointing device 78 may be separatefrom the computer 72 or they may be integral to it. A computer mouse orother device that points to or otherwise identifies a location, action,etc., e.g., by a point and click method or some other method, areexamples of a pointing device. Alternatively, a touch screen (not shown)may be used in place of the keyboard 76 and pointing device 78. A touchscreen is well known by those skilled in the art and will not bedescribed in detail herein. Briefly, a touch screen implements a thintransparent membrane over the viewing area of the display 74. Touchingthe viewing area sends a signal to the computer 72 indicative of thelocation touched on the screen. The computer 72 may equate the signal ina manner equivalent to a pointing device and act accordingly. Forexample, an object on the display 74 may be designated in software ashaving a particular function (e.g., view a different screen). Touchingthe object may have the same effect as directing the pointing device 78over the object and selecting the object with the pointing device, e.g.,by clicking a mouse. Touch screens may be beneficial when the availablespace for a keyboard 76 and/or a pointing device 78 is limited.

Included in the computer 72 is a storage medium 80 for storinginformation, such as application data, screen information, programs,etc. The storage medium 80 may be a hard drive, for example. A processor82, such as an AMD Athlon 64™ processor or an Intel Pentium IV®processor, combined with a memory 84 and the storage medium 80 executeprograms to perform various functions, such as data entry, numericalcalculations, screen display, system setup, etc. A network interfacecard (NIC) 86 allows the computer 72 to communicate with devicesexternal to the system 6.

The actual code for performing the functions described herein can bereadily programmed by a person having ordinary skill in the art ofcomputer programming in any of a number of conventional programminglanguages based on the disclosure herein. Consequently, further detailas to the particular code itself has been omitted for sake of brevity.

As will be appreciated, the various computer codes for carrying our theprocesses herein described can be embodied in computer-readable media.In addition, the various methods and apparatus herein described can be,individually or collectively, supplemented with one or more of thevarious methods and apparatus described in U.S. patent application Ser.Nos. 10/464,809, 10/661,827, 11/115,093, 10/753,979, 10/771,545,10/442,989 and 09/745,039, and in U.S. Pat. Nos. 6,464,662, 6,549,803and 6,572,579, except to which such methods and apparatus areinconsistent with the herein described methods and apparatus. All of theaforesaid patent applications and patents are herein incorporated byreference in their entireties.

Although the invention has been shown and described with respect to acertain preferred embodiment or embodiments, it is obvious thatequivalent alterations and modifications will occur to others skilled inthe art upon the reading and understanding of this specification and theannexed drawings. In particular regard to the various functionsperformed by the above described elements (components, assemblies,devices, compositions, etc.), the terms (including a reference to a“means”) used to describe such elements are intended to correspond,unless otherwise indicated, to any element which performs the specifiedfunction of the described element (i.e., that is functionallyequivalent), even though not structurally equivalent to the disclosedstructure which performs the function in the herein illustratedexemplary embodiment or embodiments of the invention. In addition, whilea particular feature of the invention may have been described above withrespect to only one or more of several illustrated embodiments, suchfeature may be combined with one or more other features of the otherembodiments, as may be desired and advantageous for any given orparticular application.

1. A method for treating ALS by delivery of an agent within the brain,the method comprising the steps of: identifying a target region of thebrain; and planning a delivery by infusion of the agent to the targetregion of the brain.
 2. The method of claim 1, further comprising thestep of delivering the agent to the target region of the brain based onthe plan.
 3. The method of claim 2, further comprising the step of usingantibodies as the agent.
 4. The method of claim 2, further comprisingthe step of adjusting a flow rate of the agent based on an actualcatheter placement compared to the planned catheter placement.
 5. Themethod of claim 1, further comprising the steps of: calculating adiffusion tensor of the target region; simulating at least one of aconcentration of the agent in the target region and a distribution ofthe agent in the target region; and refining the planned catheterplacement based on the simulated agent distribution and/or the simulatedagent concentration.
 6. The method of claim 5, wherein the steps ofcalculating the diffusion tensor includes the step of using at least oneof chemical, pharmaceutical and biological properties of the agent toperform the respective calculation.
 7. The method of claim 1, furthercomprising the step of using anti-beta amyloid antibodies as the agent.8. The method of claim 1, wherein the step of identifying the targetregion of the brain includes the steps of: measuring electrical activityfrom cells within a region of the brain; identifying different celltypes based on the measured electrical activity; and identifying thetarget region to include cell types that exhibit substantially the sameelectrical activity.
 9. The method of claim 1, wherein the step ofplanning the delivery of the agent includes the steps of: acquiring atleast one three-dimensional image of the target region; acquiring atleast one magnetic resonance diffusion tensor imaging (MR-DTI) scan ofthe target region; calculating a diffusion tensor from the MR-DTI scan;and calculating at least one of a concentration of the agent in thetarget region and a distribution of the agent in the target region. 10.The method of claim 9, wherein the step of acquiring at least onethree-dimensional image of the target region includes the step ofobtaining image scans that have at least about 1 mm in-plane spatialresolution.
 11. The method of claim 9, wherein the step of calculatingat least one of the concentration of the agent and the distribution ofthe agent includes the step of simulating the concentration and/ordistribution of the agent in the target region.
 12. The method of claim11, further comprising the step of providing alternate catheterpositions to provide simulation results that meet a specified criteria.13. The method of claim 1, further comprising the step of providingguidelines for catheter placement.
 14. The method of claim 1, whereinthe step of delivering the agent to the target region includes the stepof delivering the agent to the target region at a specified flow rate.15. The method of claim 13, further comprising the step of limiting theflow rate to be less than about seven micro-liters per minute.
 16. Themethod of claim 13, further comprising the step of limiting the flowrate such that a back flow of the agent is less than about threecentimeters from a delivery point of the agent.
 17. The method of claim1, further comprising the step of delivering the agent to the targetregion by diffusion.
 18. A method for treating ALS by delivery of anagent within the brain, the method comprising the steps of: acquiring atleast one image of a target region; acquiring at least one magneticresonance diffusion tensor imaging (MR-DTI) scans of the target region;calculating a diffusion tensor from the at least one MR-DTI scan;calculating at least one of an agent distribution and an agentconcentration from the images and the calculated diffusion tensor; andusing at least one of the calculated diffusion tensor, the images, thecalculated agent distribution, and the calculated agent concentration toplan the placement of a delivery instrument to deliver the agent to thetarget region to achieve a desired agent concentration and/or agentdistribution within the target region.
 19. The method of claim 18,further comprising the steps of: acquiring data relating to individualanatomy and/or physiology of the patient; and using at least one of theanatomy data, the physiology data, the image scans, the MR-DTI scans,the calculated diffusion tensor, the calculated agent concentration andthe calculated agent distribution to perform a simulation of the agentconcentration and/or the agent distribution.
 20. The method of claim 18,further comprising the steps of: simulating at least one of aconcentration of the agent in the target region and a distribution ofthe agent in the target region; and refining the planned catheterplacement based on the simulated agent distribution and/or the simulatedagent concentration.
 21. A program embodied in a computer-readablemedium for treating ALS by delivering an agent within the brain,comprising: code that identifies a target region of the brain; and codethat plans a delivery by infusion of the agent to the target region ofthe brain.
 22. A system for treating ALS by delivering an agent withinthe brain, comprising: a processor circuit having a processor and amemory; a treatment sub-system stored in the memory and executable bythe processor, the treatment sub-system comprising: logic thatidentifies a target region of the brain; and logic that plans a deliveryby infusion of the agent to the target region of the brain.